Proteoglycans are abundant on the surface of epidermal keratinocytes, but their function is unknown. Cell-cell adhesive interactions play a central role in normal and pathologic tissue organization. Epican, a newly discovered heparan sulfate form of CD44, has been found on keratinocytes and preliminary data indicate that epican could function as an adhesion molecule on keratinocytes. The aims of this proposal are to: I. Dissect the molecular basis for epican-mediated keratinocyte- keratinocyte adhesion. We propose to a) determine the role in adhesion of hyaluronic acid, the covalently-linked heparan sulfate and the N- linked sugars; b) identify the binding site on the epican core protein either by creating deletion mutants of epican that prevent binding of transfectants to keratinocytes or by using panels of synthetic peptides and/or domain-specific monoclonal antibodies to block cell-cell adhesion; II. Determine the functional consequences of epican expression on keratinocytes. We propose to test the role of epican in a) cell-cell and cell-matrix adhesion b) growth regulation and c) cell and tissue morphology by overpressing epican in spontaneous keratinocyte lines that express low levels of epican. III. Determine that functional consequences of epican expression on melanocytes by examining a) the conditions under which epican is expressed on melanocytes; b) the effects of epican expression on growth, morphology and adhesive characteristics of melanocytes or melanoma cells.